The traditional concept that no regrowth of nerve processes occurs in the mammalian CNS is being discarded in the light of new evidence. Three biennial meetings of researchers into central nervous regeneration, held under the auspices of the National Paraplegia Foundation, have been instrumental in confirming that capacity for regrowth exists in the adult mammalian central nervous system, however inadequate that regrowth happens to be. This continuing Project can be divided into two parts: (a) making a study of the central microenvironment to determine what factors could influence CNS regeneration and (b) attacking the important problem of improving the chances ofeffective regeneration by testing agents that might enhance the nerve growth response after CNS lesions. The principal tool that will be used forevaluation is the electron microscope. We are carrying out studies of reorganization in a number of CNS models where partial deafferentation is feasible. These include the lateral vestibular nucleus and the ascending noradrenergic pathways in the brain stem. Detailed observations and comparisons of cellular responses are being made to obtain clues about the regulatory mechanisms involved in the post-lesion reorganization process. In addition, we are testing the hypothesis that hormones may facilitate growth of nerve fibers at the edge of a cerebral lesion; and that they also influence the glial response. The electron microscope allows individual sprouts and other cytological elements to be visualized, after their hormonal environment has been manipulated. We are also testing certain agents including NGF and hyaluronidase directly in vivo by instilling the substance into a lesion site in the CNS and assaying nerve growth and associated responses with the electron microscope. Wherever preliminary observations warrant it, we will make a detailed study of cellular interrelationships and all observable "plastic changes" by using montages to study these features after different survival periods.